Aberrant intestinal inflammation plays a critical role in the development of colitis-associated colorectal cancer (CAC), yet the mechanisms controlling tumor development by the myeloid immune compartment are not fully understood. Although altered microRNA expression is observed in CAC, it is also unclear how myeloid-specific microRNAs impact the inflammatory process that underpins the continuum from ulcerative colitis to tumorigenesis. In this study, we report that miR-223 acts to limit myeloid-driven inflammation in the azoxymethane (AOM)–dextran sodium sulfate (DSS) model of CAC in mice. In this model, miR-223–/y mice present with significantly larger tumors with an enhanced proliferative signature. Immunoprofiling showed that miR-223–/y mice have significantly increased colonic myeloid immune infiltrate (neutrophils, monocytes, and macrophages) following AOM-DSS. This was accompanied by an increased inflammatory chemokine and cytokine signature for monocytes and neutrophils. Bone marrow chimera studies demonstrate that myeloid-expressed miR-223 is responsible for the enhanced tumor proliferation and inflammatory response. RNA sequencing identified several pathways that could be contributing to the development of CAC in miR-223–/y mice, including the IL-6/IL-17a cytokine family and STAT3 signaling. Lastly, neutrophil depletion with an anti-GR1 Ab (Ly6G/Ly6C) during the initial phase of the AOM-DSS model reduced the tumor burden in miR-223–/y mice. Collectively, our data indicate that miR-223 is an important regulator of mucosal inflammation and acts to constrain the progression from ulcerative colitis to CAC by limiting myeloid-associated inflammation.



Summary

This study reveals that microRNA-223 (miR-223) plays a crucial role in suppressing myeloid-driven inflammation in a mouse model of colitis-associated colorectal cancer (CAC). Mice lacking miR-223 developed larger tumors and exhibited increased infiltration of inflammatory myeloid cells (neutrophils, monocytes, macrophages) in the colon, along with elevated inflammatory chemokine and cytokine production. Bone marrow chimera studies confirmed that myeloid-expressed miR-223 is responsible for this effect. Depleting neutrophils reduced tumor burden in miR-223 deficient mice. The findings suggest miR-223 acts as a key regulator, limiting the progression from ulcerative colitis to CAC by controlling myeloid-associated inflammation, potentially through pathways like IL-6/IL-17a and STAT3 signaling.

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